Theory of cancer evolution Flashcards
ulceration of skin from tumour seen in …
melanoma
key features of malignant tumours (4)
- Multiple mutations
- Disorganised growth
- Loss of function
- Intensive angiogenesis
H1 of evolution in cancer:
‘cells in malignant tumours evolve by natural selection’
immune cells cant see tumours due to …
escaping immunosurveillance
multi-step tumorigenesis, 3 examples;
(1) somatic mutation (occurs in NORMAL tissue)
(2) PRE-CANCER/malignancy (genetic diversity leading to malignancy
(3) somatic evolution in CANCER itself
Why humans have more cancer than other species?
- long reproductive lifespan
- mis-matched to risk factors (high-calorie/fat, pollution etc.) - not evolved for this lifestyle
- highly adaptive placenta, made by stem cells, which are pre-adapted to metastasis
high or low prevalence of covert (sub-clinical) cancer?
HIGH
e.g. cancer found in autopsies (almost 50% of males dies with prostate cancer)
e.g. covert malignant cancers
e.g. pre-malignant carcinomas in-situ found in autopsies
The cancer lottery dependant on … (3)
- if mutations occur in stem cells (already have ability to proliferate and divide) - so chance of cancer is increased
- modulators of risk
e.g. cancer susceptibility loci (pre-disposed to cancer - inherited), diet, immune system - chance
Somatic mutation theory (SMT) of cancer
(two-hit hypothesis)
genetic change in single cell
vvv
passed onto progeny
vvv
= clone of cells
vvv
further mutations acquired
vvv
sub-clone emerges - that can grow + metastasise = death of host
the two-hit hypothesis shows …
somatic mutation alone is not a driving force of cancer
micro-evolution e.g.
antibiotic resistance (occurs in population)
macro-evolution e.g.
speciation (occurs at/above level of the species)
gradualism
gradual changes in phenotype of (cancer) cell
punctuated equilibrium
immediate/massive change that leads speciation
somatic evolution =
accumulation of mutations in somatic cells over a lifetime
(NOT germ & stem cells)
these mutations increase with age/risk exposures
varient allele frequency
how many cells/clones have a certain mutation
clone
set of cells that descend from a common ancestor cell (distinguished by distinctive cell lesion inherited from the ancestor cell)
Neoplastic progression
evolutionary process, normal tissue changes into malignant tissue
shannon index define:
estimates genetic diversity (describes variation at multiple levels of genetic organisation (e.g. SNPs t ecosystems)
divergence define:
measures amount of diversity in a clone
/
assesses the genetic differences that have accumulated between clones
driver mutation =
gives selective advantage to a clone in microenvironment
(tend to cause clonal expansions)
passenger mutation =
has no effect on fitness of clone
can be a hitchhiker - occurs in the same genome with a driver mutation - associated with clonal expansion
trisomy
= 3 copies of a Chr
(hallmark of B cell malignancies)
mechanisms that create diversity (4)
- numerical chromosomal instability
- structural chromosomal instability
- somatic mutagenesis
- epigenetic heterogeneity
